Malignancies of B lymphocytes, termed non-Hodgkin leukemias and lymphomas (NHL), are among the most common cancers of adults. They develop when physiologic process of normal B cells are misdirected, leading to the activation of cancer causing genes, termed oncogenes. Studies of NHL have provided insights into the workings of normal B cells just as studies of normal cells have contributed to our understandings of NHL. Our studies have shown that certain strains of mice, some unique to our laboratory, develop a high frequency of NHL. Using combined criteria based on pathology and molecular features, we have been able to identify distinct subsets of these tumors and to show that some share many features with specific classes of human NHL. These observations were central to the development of a new consensus classification of mouse NHL that is being used internationally. This system has been invaluable for understanding the cell types targeted by specific oncogenes including Myc, Evi3 (Zfp521), Blm and Tcl1, all of which are implicated in the development of human NHL. We have also clarified how two genes that normally function to control cell death pathways, Fas and Bcl2, can contribute to the development of unique subsets of NHL. Comparative studies of these lymphomas and normal B cells have also led to new insights into previously unappreciated pathways controlling normal B cell differentiation and function including the activities of Atm, Irf8 and Il21. In particular, we have shown that IRF8 plays a major role in the germinal center reaction by driving the expression of two critical genes, BCL6 and AID. In addition, studies of normal B cell differentiation have provided new insights into the mechanisms involved in positive and negative selection. Furthermore, preliminary studies have shown that B cell transformation can be driven by mutations in proteins comprising the extracellular matrix. In additional collaborative studies, we have identified catalytic antibodies that may contribute to the pathogenesis of multiple sclerosis and other that are capable of cleaving HIV gp120. Finally, we have identified tumors that reflect sequential changes in normal plasma cell development and have suggested that they may point to the existance of a"cancer sem cell" in the etiology of plasma cell neoplasms of mice and humans. Understanding the signals driving normal B cells and the aberrations resulting in tumor development or autoimmunity will be important in understanding how B cells respond to infectious agents or self antigens. This knowledge is fundamental to developing vaccines for protective immunity and avoiding autoimmune diseases.